We recently identified the leucine zipper protein Par-4 (prostate apoptosis response-4) as a novel cell death promoting protein associated with pathogenesis of Alzheimer's disease (AD). Importantly, we have found that Par-4 may participate in regulation of Abeta production through a caspase-dependent pathway in transfected IMR-32 cells (Guo Q. et al., Nature Medicine 1998; 4(8): 957-962, Guo Q. et al., J. Biol. Chem., 2001; 276: 16040-4). Disruption of intracellular calcium homeostasis may lead to aberrant induction of Par-4 and abnormal processing of beta amyloid precursor protein (APP). These data suggest that Par-4 may be a novel regulator of APP processing. Most recently, we found that Par-4 interacts directly with APP, and alter Abeta secretion. These data strongly indicate that Par-4 regulates APP processing by at least two different mechanisms: (a) by caspase- and calcium-dependent pathways that is activated during apoptotic process, and (b) through direct physical interaction with APP. AATF is a novel leucine zipper protein that is expressed in neurons. We found AATF binds directly to Par-4 and confers neuroprotective actions, indicating that AATF might be an endogenous regulator of Par-4 activity. The proposed studies will employ a series of in vitro and in vivo approaches to test the following hypotheses: (1) Par-4 plays an essential role in aberrant APP processing of APP after initiation of apoptotic cascades; (2) Par-4 alters APP processing during apoptosis through a calcium-dependent pathway; (3) Par-4 directly interacts with APP and alters intracellular Abeta production and/or extracellular pool of secreted APPs and Abeta under apoptotic and/or nonapoptotic conditions; (4) AATF is a novel interaction partner of Par-4 and functions as an endogenous negative regulator of Par-4 activity in APP processing. The proposed studies may establish Par-4 as a novel regulator of APP processing. Inhibition of Par-4 activity by enhancing AATF expression and/or manipulating Par-4/APP interaction may provide novel therapeutic implications for Alzheimer's disease.